We have cloned a highly unusual new member of the cell growth and differentiation controlling receptor tyrosine kinase family, called ltk, which is specifically expressed in adult mouse forebrain neurons and pre-B lymphocytes. Because ltk is likely to control important signalling pathways, the further analysis of this receptor as proposed by us may not only improve the understanding of lymphoid and neuronal biology, but also provide clues about causes of neuronal and lymphoid disorders. The specific aims of our proposed research are: 1. To confirm that lymphoid and neuronal ltk cDNAs predict proteins with largely different extracellular domains. This unprecedented finding suggests that ltk may be the receptor for different lymphoid and neuronal ligands. We shall also expand on our finding that lymphoid ltk is not expressed on the surface of transfected cells. We attribute this lack of surface expression to the absence of an essential subunits, leading to incorrect receptor assembly. We shall test whether transfected neuronal ltk is cytoplasmic, and whether additional lymphoid and neuronal cDNAs restore surface expression ltk. 2. To analyze the signaling pathways in which ltk functions, by creating ltk deficient mice via ES cell gene targeting. These mice may reveal whether lymphoid ltk is the receptor for a pre-B cell growth or differentiation factor. Such a factor might be a useful therapeutic agent for B cell malignancies. If our speculative hypothesis that ltk controls the survival of cells is correct, ltk-deficient mice may show progressive neurodegeneration and provide clues about human neurodegenerative disorders. 3. To use the highly expression of ltk, to identify nuclear factors that are likely to control important aspects of lymphocyte and neuronal development. This work may lead to the identification of promoter elements that allow targeted gene expression in postmitotic cerebral neurons of transgenic animals.